Readily absorbable copolymer compositions for high strength sutures having enhanced strength retention post-implantation

ABSTRACT

Novel surgical sutures and novel medical devices made from novel semi-crystalline, glycolide-rich A-B-A triblock copolymers of glycolide and lactide, wherein said B-segment is a fully amorphous random copolymer of glycolide and lactide, for long term medical applications are disclosed. The novel polymer compositions are useful for long term absorbable surgical sutures, meshes and other medical devices, especially for patients with compromised healing. The novel sutures have improved properties and improved breaking strength retention, while still substantially absorbing within about a 120-day period post-implantation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of co-pending U.S.application Ser. No. 16/021,322 filed on Jun. 28, 2018, the completedisclosure of which is hereby incorporated herein by reference for allpurposes.

FIELD OF THE INVENTION

This invention relates to novel absorbable sutures made from novelsemi-crystalline, segmented A-B-A block copolymers of glycolide andlactide for longer term absorbable medical applications, and otherimplantable medical devices having enhanced strength retentionpost-implantation; the invention also relates to novel processes formaking such sutures and copolymers.

BACKGROUND OF THE INVENTION

Synthetic absorbable polyesters are well known in the art. The open andpatent literature particularly describe absorbable polymers andcopolymers made from glycolide, L(−)-lactide, D(+)-lactide,meso-lactide, epsilon-caprolactone, p-dioxanone, trimethylene carbonate,and combinations thereof. The term absorbable is meant to be a genericterm, which may also include bioabsorbable, resorbable, bioresorbable,degradable or biodegradable.

One very important application of absorbable polyesters is their use assurgical sutures. Absorbable sutures generally come in two basic forms,multifilament braids and monofilament fibers. Absorbable multifilamentsutures have been made from glycolide homopolymer and lactide/glycolidecopolymers. A very important aspect of any absorbable medical device isthe length of time that its mechanical properties are retained in vivo.For example, in some surgical applications it is important for themedical device to retain strength for a considerable length of time toallow the body the time necessary to heal while performing its desiredfunction. This is often referred to as Breaking Strength Retention(BSR). Sutures having longer BSR are particularly needed when addressingwound closure for patients having compromised healing. These includediabetic patients, geriatric patients, and possibly patients underchemotherapy. A need also exists in wound closure of bodily areas havingpoor or diminished blood supply.

Absorbable sutures with longer BSR are known and have been made fromconventional polymers, and include, but are not limited to,multifilament (braided) sutures made from lactide-rich lactide/glycolidecopolymers and monofilament sutures made from polydioxanone polymers.Although absorbable sutures with longer BSR are available, braidedsutures made from lactide-rich lactide/glycolide copolymers exhibitsignificantly long total absorption time which can lead to undesirableoutcomes. In addition, monofilament sutures with longer BSR exhibitrelatively inferior handling and knot security properties due to theirrelatively higher stiffness and also typically exhibit significantlylower initial tensile strength compared to braided sutures. Thoseskilled in the art will appreciate that monofilament and multifilamentabsorbable sutures exist and that short term and long term absorbablesutures exist, and such sutures are available to the surgeon. However,there is a need for an absorbable polymer that can be made into anabsorbable medical device such as a suture, wherein the suture wouldhave a combination of high initial tensile strength, superb handling andfirst throw hold, good knot sliding and knot security, and long BSRperformance for slow wound healing applications, and yet demonstratescomplete absorption in a relatively short time, approximately 18 weeksor less. There is also a need for processes for converting suchabsorbable polymers into medical devices having these properties,including sutures.

Crystalline block copolymers of glycolide and lactide are disclosed inU.S. Pat. Nos. 6,007,565 and 6,136,018 (Roby et al.). The copolymersdisclosed in these patents are described as preferably composed of twoblocks (A-B type), with the first block containing from about 60 to 35mole percent of glycolide randomly combined with from about 60 to 35mole percent of lactide repeat units. The first block is described topreferably contain from about 40 to about 45 mole percent of lactic acidester linkages. The second block is described as containing bothglycolide and lactide repeating units, with a higher proportion ofglycolide than the first block. The glycolide concentration in theentire copolymer ranges from about 75 to about 95 mole percent. Althoughthe BSR properties of fibers made by these copolymers are somewhatlonger than corresponding random glycolide and lactide copolymercompositions, they are vastly inferior to the BSR performance of thefibers made from the copolymers of the present invention, as will beshown later in the experimental section. Although a difunctionalinitiator was mentioned in the text as a possibility, Roby et al. failedto recognize the criticality in having an A-B-A block copolymerstructure versus an A-B type, providing for a “B” segment center block(CB) composition that would allow for extra-long BSR properties.Furthermore, processing conditions (synthesis and extrusion) asdescribed in both references are found to be inadequate in producingfibers that exhibit longer BSR properties.

Similarly, U.S. Pat. No. 4,243,775 teaches a method for the manufactureof surgical articles made from synthetic absorbable copolymers formed bycopolymerizing glycolide as the predominant monomer with a cyclic esterother than glycolide employing sequential addition of the monomers inthe polymerization. This reference teaches that, preferably, the cyclicester monomer is lactide. One of the preferred embodiments includestriblock structures formed by sequentially and consecutivelycopolymerizing L(−)-lactide, glycolide, and again L(−)-lactide. Thecopolymer produced from this method has lactic acid units predominatingon both ends of the glycolide CB polymer chain. In addition, it isbelieved that the presence of lactide moieties in the end blocks wouldreduce crystallization and therefore would very likely reduce the suturetensile strength. These structures, again, would not be suitable forlong BSR suture applications.

Completely amorphous, biodegradable multi-block copolymers composed of avariety of lactone moieties including glycolide and lactide aredescribed in U.S. Pat. No. 8,481,651B2. These copolymers have soft chainsegments due to the absence of crystallinity and possess relatively lowglass transition temperature. Thus, they cannot be used to producestrong sutures with long BSR properties and sufficient dimensionalstability due to the lack of crystallinity and relatively low glasstransition temperature.

U.S. Pat. No. 6,770,717 describes a biodegradable multi-block copolymer,whose repeat units, in addition to glycolide and glycolide/lactidecombinations, contain poly(epsilon-caprolactone) (PCL) moieties. Thepresence of flexible and hydrophobic PCL units may improve elasticityand increase material hydrophobicity for tissue engineeringapplications, however, the significantly lower crystallinity wouldresult in a suture device with lower tensile strength.

Absorbable multi-block compositions, wherein the first block is apoly(lactide-glycolide) and the second block is a member of the groupconsisting of lactide-glycolide copolymer having a higher percentage oflactide than the first block, are described in US 2009/304767. Thesehigh lactide block or graft compositions contain a first block having alactide:glycolide ratio in the range of 25:75 to 60:40, and a secondblock having a lactide:glycolide ratio in the range of 70:30 to 99:1.These low crystallinity, low strength compositions may be suitable forcoatings, scaffolds, and/or drug delivery carriers, but not for highstrength long term suture applications.

U.S. Pat. No. 5,236,444 relates to absorbable block copolymers andsurgical articles therefrom having a block that is predominately madefrom polymerized glycolide, and a block that has glycolide, lactide andtrimethylene carbonate linkages. The presence of trimethylene carbonatein these A-B structures provides increased elasticity for monofilamentsuture use, but lowers tensile strength and increases the hydrolysisrate, which negatively affects BSR performance.

In summary, there is an unmet need in this art for novel absorbablesutures having a combination of good handling characteristics, highinitial tensile strength, long BSR properties post-implantation, and arelatively short total absorption time of preferably 120 days or less.There is a further need in this art for novel absorbable polymer systemsfor manufacturing such sutures and other absorbable medical deviceshaving these desirable characteristics.

SUMMARY OF THE INVENTION

Novel semi-crystalline, glycolide-rich block copolymers of glycolide andlactide of the structure A-B-A for longer term absorbable medicalapplications are disclosed. The absorbable copolymers have a structureA-B-A comprising end segments A and middle segment B. The end-segments Acomprise polymerized glycolide and the middle segment B comprisespolymerized glycolide and polymerized lactide. The middle segment B isfully amorphous and contains about 30 mole percent to about 80 molepercent of polymerized lactide, and about 20 mole percent to about 70mole percent of polymerized glycolide. The total amount of polymerizedglycolide in the absorbable copolymer is about 88 mole percent to about92 mole percent of the absorbable copolymer and the total amount ofpolymerized lactide is about 8 mole percent to about 12 mole percent ofthe absorbable copolymer.

Another aspect of the present invention is an absorbable medical devicemade from an absorbable copolymer of the structure A-B-A comprising endsegments A and middle segment B. The end-segments A comprise polymerizedglycolide and the middle segment B comprises polymerized glycolide andpolymerized lactide. The middle segment B is fully amorphous andcontains about 30 mole percent to about 80 mole percent of polymerizedlactide, and about 20 mole percent to about 70 mole percent ofpolymerized glycolide. The total amount of polymerized glycolide in theabsorbable copolymer is about 88 mole percent to about 92 mole percentof said absorbable copolymer and the total amount of polymerized lactideis about 8 mole percent to about 12 mole percent of said absorbablecopolymer.

Yet another aspect of the present invention is a method of extruding thenovel copolymers of the present invention into multifilament yarns.

Still yet another aspect of the present invention is a method ofmanufacturing a medical device from said novel copolymers.

Surprisingly and unexpectedly, multifilaments made from the segmented,glycolide-rich, poly(glycolide-co-lactide) copolymers having an A-B-Atype structure of the present invention, exhibit exceptionally long BSRproperties, while also exhibiting a total absorption time, for example,of 18 weeks or less.

These and other aspects and advantages of the present invention willbecome more apparent from the following description and accompanyingfigures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is graph showing Weight Average Molecular Weight (Mw) of theA-B-A Polymers of Examples 3-12 vs. B-Segment Composition.

FIG. 2 is a graph showing Inherent Viscosity (IV) of the A-B-A Polymersof Examples 3-12 vs. B-Segment Composition.

FIG. 3 is a graph of Average Chain Sequence Length of Lactoyl Units(ACLSL) of the A-B-A Polymers of Examples 5-12 vs. Mole PercentPolymerized Lactide in the B-Segment.

FIG. 4 is a graph of Straight Tensile Breaking Strength Retention (BSR)of Size 2-0 Braids Made from the A-B-A Polymers of Examples 3-12 vs.B-Segment Composition.

FIG. 5 is a graph of Tensile Strength of Size 2-0 Braids Made From theA-B-A Polymers of Examples 3-12 vs. “B” Segment Composition.

FIGS. 6A and 6B are graphs showing The First Stage Monomer Consumptionby Real-Time FT-NIR Spectroscopy for Example 16: A) Area Under theMonomers' Peaks as a Function of Reaction Time; and, B) MonomerConsumption in Percentages as a Function of Time.

FIG. 7 is a graph showing the Second Stage Glycolide Conversion forExamples 15-17.

FIG. 8A is a graph showing In Vitro Straight Tensile Percent BSR of a2-0 Braid of the Current Invention (Made from the A-B-A Copolymer ofExample 15), and 2-0 Braids Based on Prior Art Teachings (Made from theCopolymers of Examples 19-21).

FIG. 8B is a graph showing In Vitro Straight Tensile BSR, in Pounds, ofa 2-0 Braid of the Current Invention (Made from the A-B-A Copolymer ofExample 15), and 2-0 Braids Based on Prior Art Teachings (Made from theCopolymers of Examples 19-21).

FIG. 9A is a graph showing In Vitro Knot Tensile Percent BSR of a 2-0Braid of the Current Invention (Made from the A-B-A Copolymer of Example15), and 2-0 Braids Based on Prior Art Teachings (Made from theCopolymers of Examples 19-21).

FIG. 9B is a graph showing In Vitro Knot Tensile BSR, in Pounds, of a2-0 Braid of the Current Invention (Made from the A-B-A Copolymer ofExample 15), and 2-0 Braids Based on Prior Art Teachings (Made from theCopolymers of Examples 19-21).

FIG. 10 is a graph showing In Vitro Straight Tensile BSR, in Pounds, ofa Size 2 Braid of the Current Invention (Made from the A-B-A Copolymerof Example 15).

DETAILED DESCRIPTION OF INVENTION

The present invention is directed toward novel copolymers of glycolideand lactide and novel medical devices, particularly sutures, made fromsuch copolymers having surprising and unexpected properties. Morespecifically, this class of copolymers rich in glycolide is made to havea blocky sequence distribution that is non-random and of an A-B-A type.In glycolide and lactide copolymers in which most of the material isbased on glycolide, the glycolide containing end segments (“A”) need tobe as pure as possible to allow fast crystallization, as well as highcrystallinity level. On the other hand, an amorphous center block(B-segment) needs to be rich in lactide to increase the hydrophobicityof the amorphous region, which slows the rate hydrolysis, and ultimatelyresults in longer BSR.

Dimensional stability in a fiber used to manufacture a surgical sutureis critically important to prevent shrinkage, both in the sterilepackage before use, as well as after surgical implantation in thepatient's body (i.e., in vivo). Although the overall level ofcrystallinity and glass transition temperature (Tg) of the materialplays a role in dimensional stability, it is important to realize thatthe rate of crystallization is also critical to processing. If aslow-to-crystallize material is processed, it is very difficult toachieve a desired level of crystallinity and desired molecularorientation during processing, which therefore, could reduce the tensilestrength of a fiber. To increase the rate of crystallization of acopolymer of given overall chemical composition, a block structure,particularly of A-B-A type would be preferable over a random sequencedistribution. In addition, it will be shown herein below that minimizingtransesterification reactions to maintain the A-B-A chain structureduring processing is critical to achieving longer BSR properties of themanufactured device.

We have unexpectedly discovered that the following polymer chainsequence, polymer formulation, and polymerization attributes contributegreatly and significantly to long BSR performance in glycolide-richglycolide/lactide copolymers: a) A-B-A block copolymer architectureinstead of A-B type, with an amorphous B-segment containing about 30mole percent to 80 mole percent of polymerized lactide and 20 molepercent to 70 mole percent of polymerized glycolide; b) less than 2 molepercent unreacted lactide monomer at the completion of the prepolymer(B-segment) polymerization; c) a catalyst ratio (moles of monomers:molesof catalyst) in the range between 50,000:1 to 300,000:1; d) diol as aninitiator with an initiator ratio (moles of monomers:moles of initiator)between 500:1 to 1,500:1; e) fast agitation in the mixing period of thesecond polymerization stage; and, f) controlled exotherm and relativelylow reactor batch temperature during the second polymerization stage.

The novel A-B-A segmented copolymers of the present invention can beprepared by a two-stage polymerization reaction in which alactide/glycolide prepolymer is polymerized in the first stage to makethe B-segment, and a second stage that consists of polymerizingadditional glycolide off of both ends of the B-segment prepolymer tomake the A-segments of the final A-B-A polymer. More specifically, thefirst stage involves polymerizing all of the lactide monomers and asmall amount of glycolide monomers at temperatures between about 170° C.and about 240° C. in a suitable, conventional reactor vessel.Temperatures between about 180° C. and about 195° C. are particularlyadvantageous. In the practice of the present invention, an initiatorthat is a diol, such as diethylene glycol, must be used for the presentformulations to work well. The concentration of a diol as an initiatordetermines the molecular weight of the final copolymer. Typically, theinitiator ratio (moles of monomer:moles of initiator) is set betweenabout 500:1 to about 1,500:1. More typically, the initiator ratio rangeis about 600:1 to about 1,200:1. Preferably, the initiator ratio rangewill be set between 750:1 to 900:1. Suitable catalysts includeconventional catalysts, such as stannous octoate. The catalyst ratios(moles monomer:moles catalyst) that may be used typically range fromabout 50,000:1 to about 300,000:1, more typically from about 75,000:1 toabout 275,000:1, with a preferred range from about 100,000:1 to about250,000:1, and the most preferred range from about 150,000:1 to about200,000:1. The reaction time in the first stage can vary depending onthe reactor temperature, but it is typically between 120 and 180minutes. The reaction time will be sufficient to effectively polymerizeboth glycolide and lactide monomers, such that the unreacted lactide atthe end of the first stage is less than about 2 mole percent.

After the completion of this first stage of the polymerization, thesecond (major) portion of glycolide can be added directly into thereactor in its powder form. Preferably, the second stage glycolide isadded in the molten form from a suitable, conventional melt tankpreheated at 120° C. During the second stage addition, the temperaturein the main reactor can be maintained at the temperature of the firstpolymerization stage, preferably between 175° C. and 195° C., until themixing of the added glycolide with a prepolymer is completed.Alternately, once the major portion of glycolide monomer is added, thetemperature can be brought to a range of about 200° C. to about 210° C.,maintained at this temperature for a sufficiently effective period oftime (e.g., about 30 to 90 minutes), until the complete mixing stage isachieved. During the second stage polymerization, it was found that themixing speed had an impact on final polymer properties. After the secondstage glycolide monomer is added to the reactor, a sufficientlyeffective high mixing speed is needed to ensure that the glycolidemonomer is incorporated into the prepolymer melt. It was shown that amixing (agitation) speed of between 15 RPM (rotation per minute) toabout 30 RPM for 30 to 90 minutes is sufficiently effective for the typeof reactor that was used in this study for complete mixing of the addedglycolide monomer and prepolymer melts.

The second stage total reaction time will be sufficiently effective topolymerize the glycolide monomer added in the second stage off both endsof the prepolymer chains thus creating an A-B-A chain sequence, and canvary from about 100 minutes to about 200 minutes from the time ofglycolide addition. The batch temperature in the second stage will besufficiently effective to polymerize second stage glycolide, and may bekept at about 200° C. to about 230° C. Preferably, the batch temperaturein the second polymerization stage should be maintained between 205° C.and 215° C. The optimal second stage reaction time may be approximately150 minutes to 240 minutes from the glycolide addition. The agitationspeed after the mixing period is over can be reduced to a sufficientlyeffective speed, for example, about 5 RPM to about 10 RPM, until the endof reaction. Lower agitation speeds at the later stages of the reactionwere found to help in reducing the degradation and/ortransesterification reactions.

Polymerized resin from the reactor can be discharged into multipleconventional containers and stored in a nitrogen flow equippedconventional oven, or placed in a conventional freezer until furtherprocessing. The copolymer resin discharged in this fashion requiresadditional grinding and sieving operations before drying. Preferably,the polymerized resin can be discharged through a conventionalpelletization step, such as underwater pelletization, and then theresulting produced pellets can be stored in the freezer, or in the ovenunder nitrogen atmosphere prior further use.

Polymer drying and devolatilization is usually the final step in thepolymer synthesis. This step is needed to remove water (from underwaterpelletization) and unreacted monomers from the polymer. If the unreactedmonomers are not removed, undesirable consequences could result in bothdownstream processing and in the final medical device, such as increasedtissue reaction and accelerated in vivo degradation leading to poor BSRperformance. A twin shell, oil-heated Patterson-Kelly tumble dryer, orequivalent, can be conveniently used for devolatilization of monomersand moisture. Alternatively, a Fluidized Bed Dryer (FBD) can be used forthe same purpose. It is believed that there is no discernible differencebetween the two processes other than somewhat improved cycle time usingthe FBD.

A typical tumble dryer process includes a vacuum drying cycle with thefollowing heating steps, operated at vacuum levels <250 mTorr: a) 18hours ambient; b) 24 hours heated @ 140° C.; and, c) four hours ofcooling down. This drying cycle is proven to be effective in removingunreacted monomer, and the drying efficiency is comparable to thefluidized bed dryers. Alternatively, a lower temperature drying cyclecan be used as well: a) 10 hours ambient; b) 40-48 hours heated @ 120°C.; and, c) four hours of cooling down. The dryer process conditionswill be sufficient to effectively remove unreacted monomers.

It will be evident to one skilled in the art that various alternatepolymerization approaches are possible that will produce the copolymersof the present invention. For example, the polymerization of theamorphous glycolide/lactide prepolymer (B-segment) can be madeseparately in a larger amount, stored, and used at a later time tocomplete the overall polymerization, in which the prepolymer isre-heated and the glycolide monomer required for the A-segments is addedto perform the second stage of the reaction. Again, one skilled in theart can provide a variety of alternate and effective polymerizationschemes.

Poly(glycolide-co-lactide) copolymers comprising a polymerized glycolidehaving a total molar level between about 88 percent to about 92 percentand a polymerized lactide molar level between about 8 percent to about12 percent are particularly useful in the practice of the presentinvention. This class of copolymers, the poly(glycolide-co-lactide)family rich in glycolide, will preferably contain about 10 mole percentof polymerized lactide.

The copolymers of the present invention are semicrystalline in nature,having a crystallinity level ranging typically from about 30 to about 55percent, more typically about 35 to about 45 percent, and preferablyabout 38 to about 42 percent. The copolymers will have a molecularweight sufficiently high to allow the medical devices made therefrom toeffectively have the mechanical properties needed to perform theirintended function. Typically, for example, the molecular weight of thecopolymers of the subject invention will be such so as to exhibitinherent viscosities (IV) as measured in hexafluoroisopropanol (HFIP, orhexafluoro-2-propanol) at 25° C. and at a concentration of 0.1 g/dLtypically between about 1.2 dL/g to about 2.5 dL/g. More typically, theIV range can be between about 1.25 dL/g to about 1.8 dL/g, and mostpreferably between about 1.3 dL/g to about 1.6 dL/g.

The copolymers of the subject invention can be melt extruded by avariety of processing means. Multifilament fiber formation can beaccomplished by different means. Monofilament fiber formation is alsopossible by melt extrusion followed by extrudate drawing with or withoutannealing. Methods of manufacturing monofilament and multifilamentbraided sutures are disclosed in U.S. Pat. No. 5,133,739, entitled“Segmented Copolymers of epsilon-Caprolactone and Glycolide” and U.S.Pat. No. 6,712,838 entitled “Braided Suture with Improved Knot Strengthand Process to Produce Same”, which are incorporated by reference intheir entirety herein.

The novel surgical sutures made from the novel copolymers of the presentinvention preferably are multifilaments or braids having a BSR at42-days post-implantation greater than 10%, more preferably greater than20%, and most preferably greater than 30%. We have clearly shown (seeExample 23, FIGS. 8B and 9B) that segmented, block copolymers of 90/10poly(glycolide-co-lactide) described in the prior art (U.S. Pat. Nos.6,007,565 and 6,136,018) have BSR values at 42-days post-implantation ofonly about 5% or lower and are vastly inferior to the novel copolymersand fibers of the present invention.

In one embodiment, the medical devices made of the copolymers of thepresent invention may contain conventional active ingredients (andequivalents thereof), such as antimicrobials, antibiotics, therapeuticagents, hemostatic agents, radio-opaque materials, tissue growthfactors, and combinations thereof. Particularly useful antimicrobialsinclude Triclosan, PHMB, Octenidine, silver and silver derivatives orany other bio-active agent and the like.

In addition to sutures, the copolymers of the present invention may beused to manufacture conventional medical devices using conventionalprocesses. For example, injection molding can be used after allowing thecopolymer to crystallize in the mold; alternately, biocompatiblenucleating agents might be added to the copolymer to reduce cycle time.The medical devices may include, the following conventional devices:tissue repair fabrics, meshes, suture anchors, stents, orthopedicimplants, staples, tacks, fasteners, suture clips, etc.

Sutures made from the copolymers of the present invention may be used ina conventional manner in conventional surgical procedures andequivalents thereof, e.g., to approximate tissue or affix tissue tomedical devices. Typically, after a patient is prepared for surgery in aconventional manner, including swabbing the outer skin withantimicrobial solutions and anesthetizing the patient, the surgeon willmake the required incisions, and, after performing the requiredprocedure proceed to close the incision by approximating tissue usingthe novel sutures having longer BSR of the present invention made fromthe novel copolymers of the present invention. In addition to tissueapproximation, the sutures may be used to affix implanted medicaldevices to tissue in a conventional manner. The longer-BSR absorbablesutures of the present invention implanted in the patient retain theirstrength in vivo for an extended period of time to allow for effectivehealing and recovery.

As discussed herein, suitable synthetic absorbable polymers of thepresent invention include glycolide/lactide segmented A-B-A typecopolymers rich in glycolide, wherein the B-segment is a copolymer ofglycolide and lactide. This B-segment will typically contain betweenabout 30 mole percent and about 80 mole percent of polymerized lactideto make the B-segment fully amorphous, more typically about 40 to about70 mole percent, and preferably about 50 to about 60 mole percent.Within this class, the copolymers rich in polymerized glycolide willtypically have between about 80 to about 95 mole percent of totalpolymerized glycolide in the final copolymer, more typically about 84 toabout 93 mole percent, and preferably about 88 to about 92 mole percent.

The medical devices made from the copolymers of the present inventionmay contain, if desired, medically useful substances. The medicallyuseful substances may be incorporated into or onto the medical devicesin a variety of conventional manners including compounding, coating,spraying, dipping, sputtering and the like. If desired, the medicaldevices of the present invention may contain other conventionalmedically useful components and agents. The other components, additivesor agents will be present to provide additional desired characteristicsto the multifilament or monofilament sutures and other medical devicesof the present invention including but not limited to antimicrobialproperties, controlled drug elution, therapeutic aspects,radio-opacification, and enhanced osseointegration, etc.

Such other components, additives and agents will be present in asufficient amount to effectively provide for the desired effects orcharacteristics. Typically, the amount of the other adjuncts will beabout 0.1 weight percent to about 20 weight percent, more typicallyabout 1 weight percent to about 10 weight percent and preferably about 2weight percent to about 5 weight percent.

Examples of antimicrobial agents useful with the sutures of the presentinvention include the polychlorophenoxy phenols such as5-chloro-2-(2,4-dichlorophenoxy)phenol (also known as Triclosan).Examples of radio-opacification agents include barium sulfate whileexamples of osseointegration agents include tricalcium phosphate.

The variety of therapeutic agents that can be used with the medicaldevices and polymers systems of the present invention is vast. Ingeneral, therapeutic agents which may be administered via the medicaldevice and polymer systems pharmaceutical combinations of the presentinvention include, without limitation, antiinfectives, such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;adhesion preventatives; anticonvulsants; antidepressants; antidiureticagents; antidiarrheals; antihistamines; anti-inflammatory agents;antimigraine preparations; contraceptives; antinauseants;antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics, anti spasmodics; anticholinergics; sympathomimetics;xanthine derivatives; cardiovascular preparations including calciumchannel blockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators, including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones, such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins; oligonucleotides, antibodies, antigens, cholinergics,chemotherapeutics, hemostatics, clot dissolving agents, radioactiveagents and cystostatics. Therapeutically effective dosages may bedetermined by in vitro, in vivo clinical methods. For each particularadditive, individual determinations may be made to determine the optimaldosage required. The determination of effective dosage levels to achievethe desired result will be within the realm of one skilled in the art.The release rate of the additives may also be varied within the realm ofone skilled in the art to determine an advantageous profile, dependingon the therapeutic conditions to be treated.

Suitable glasses or ceramics that may be incorporated into the medicaldevices of the present invention include, but are not limited tophosphates such as hydroxyapatite, substituted apatites, tetracalciumphosphate, alpha-and beta-tricalcium phosphate, octacalcium phosphate,brushite, monetite, metaphosphates, pyrophosphates, phosphate glasses,carbonates, sulfates and oxides of calcium and magnesium, andcombinations thereof.

Surgical sutures made from the copolymers of the present invention mayalso include other conventional additives including colorants such aspigments and dyes, as well as radio-opaque agents, growth factors andthe like. The dyes should be generally acceptable for clinical use withabsorbable polymers; this includes, without limitation, D&C Violet No. 2and D&C Blue No. 6 and similar combinations thereof. Additional dyesthat are useful include conventional dyes useful with absorbablepolymers including D&C Green No. 6, and D&C Blue No. 6.

In addition, monofilament or multifilament sutures made from thecopolymers of the present invention may be delivered to the surgeon in avariety of lengths and diameters. Preferably, conventional surgicalneedles are mounted to one end or both ends of the sutures (i.e.,single-armed or double-armed), although the sutures may be unarmed withno surgical needles mounted.

Modern surgical sutures generally range from USP Size 5 (for example,heavy braided suture for orthopedics) to USP Size 11-0 (for example,fine monofilament suture for ophthalmics). The actual suture diameterfor a given USP size differs depending on the suture material class. Thediameters of sutures in the synthetic absorbable suture class are listedin the United States Pharmacopeia (USP) as well as in the EuropeanPharmacopoeia. The USP standard is more commonly used. The novel suturesof the present invention can be made in a variety of sizes, includingconventional suture sizes. The suture sizes of the braid sutures of thepresent invention, in general, can range from USP size 12-0 to 5.Multifilament braided sutures are constructed of filaments of thepresent invention and will have a sufficiently effective denier perfilament (dpf) to provide the desired properties, typically a dpf ofabout 0.5 to about 5.

The novel sutures of the present invention may be packaged inconventional suture packaging including polymer trays with tracks, paperfolders, etc., with a polymer and/or foil overwrap that is hermeticallysealed and impervious to moisture and microbes. The sutures will besterilized preferably in their packages using conventional medicaldevice sterilizations processes, such as ethylene oxide, radiation,autoclaving, etc. Those skilled in the art will understand that theoptimal sterilization process chosen should not adversely affect thecharacteristics of the absorbable polymeric sutures.

The novel absorbable sutures of the present invention that are made fromthe novel absorbable copolymers are preferably useful as multifilamentsurgical sutures. However, the filaments may be used in otherconventional medical devices including, but not limited to, fibrousdevices such as monofilament-based sutures and surgical fabricsincluding barbed sutures, meshes, woven fabrics, nonwoven fabrics,knitted fabrics, fibrous bundles, cords, tissue engineering substrates,and the like. The surgical meshes may be made using conventional methodsincluding knitting, weaving, air-laying, etc. Filaments of the presentinvention, when used for constructing other medical devices such asmeshes, will typically have diameters in the range of about 1 to about100 μm.

Medical devices made from the novel segmented copolymers of the presentinvention may be used in conventional surgical procedures usingconventional surgical techniques. For example, surgical sutures madefrom the novel copolymers of the present invention that are mounted toconventional surgical needles may be used to suture wounds, repair bloodvessels and organs, close incisions, attach medical devices to tissue,etc. In the case of repairing wounds or closing incisions byapproximating tissue edges about a wound or incision, the needle andsuture are passed through tissue about the wound or incision one or moretimes, and the sides of the wound are brought together by tensioning thesuture and securing it in place in a conventional manner such as withknots.

If desired, the copolymers of the present invention when made intomonofilament sutures may be processed to have barbs. Such barbs can beemplaced or incorporated in a conventional manner including cutting,molding, pre-forming, forming, attaching, etc. An example of abarb-forming process is disclosed in the U.S. Pat. No. 8,216,497 “TissueHolding Devices and Methods for Making the Same” which is incorporatedherein by reference. An alternate process of making barbed sutures is acutting process. An example of a barb-cutting process is disclosed inthe U.S. Pat. No. 7,913,365 “Method of Forming Barbs on a Suture andApparatus for Performing Same”.

Different characterization methods, described below, were used tomeasure key properties of the polymer resins, fibers, and braidsproduced to support this application.

Calorimetric data were generated on a TA Instruments' DifferentialScanning Calorimeter, DSC Model 2910 MDSC, using dry N₂ as a purge gas.Typically, about 5-10 mg of a polymer resin or a fiber was placed in analuminum pan, secured by a lid (cover), and positioned in theautosampler holder area of the instrument. Two types of non-isothermalconditions are employed: a) First heat scan: a copolymer or a fiber wasquenched to −40° C., followed by the constant heating rate at 10° C./minup to 260° C.; and, b) Second heat scan: after melting of a sample at260° C. for three minutes, a copolymer or a fiber was quenched below itsglass transition temperature (−40° C.), followed by the controlledheating step with the constant rate of 10° C./min. The first heat scandata are indicative of “as is” properties of a sample and, as such,largely dependent on its thermal history. The second heat data, on theother hand, are independent of thermal history of the sample and are afunction of the inherent properties of the sample (chemistry, molecularweight, monomer level, etc.). From the first heat scan data, in additionto the glass transition temperature and melting point, the heat offusion, ΔHm, as an area under the melting peak and expressed typicallyin J/g, can be obtained. Heat of fusion is directly proportional to thelevel of crystallinity in a sample. The TA Universal Analysis 2000(version 4.7A) software package provided by TA Instruments-Waters LLCwas used to determine all calorimetric parameters. The mid-point of thestep transition was used to obtain the glass transition data.

Morphological data were obtained by conventional Wide Angle X-RayDiffraction (WAXD) analysis. The WAXD measurements of a dried resin or afiber were carried out on a Siemens Hi-Star™ unit using CuKα radiationat a wavelength of 1.542 Å. The instrument was operated at 40 kV and 40mA with a collimator size of Ø0.5 mm. The convolution of the X-rayimages and the calculation of crystallinity content were conducted usingthe DIFFRAC PLUS™ software developed by Siemens.

Inherent viscosity, IV measurements were conducted inhexafluoroisopropanol, HFIP at 25° C. and at a concentration of 0.10g/dL. The molecular weight measurements were performed using GelPermission Chromatography equipped with Wyatt's Optilab rExrefractometer and Wyatt's HELEOS II multi-angle laser light scatteringdetector. During the measurements, PL HFIP gel columns were maintainedat 40° C., with a mobile phase consisting of HFIP with 0.01M LiBr (0.2%H₂O) operating at the flow rate of 0.7 ml/min.

Gel Permeation Chromatography (GPC) data were collected on Waters 2695,Wyatt Optilab rEx Refractometer, using Wyatt HELEOS II Multi-Angle LaserLight Scattering Detector. Empower and Astra software were used for dataanalysis. Two PL HFIP gel columns were used operated at 40° C., and HFIPwith 0.01 M LiBr (0.2% H₂O) as a mobile phase. Flow rate was 0.7 mL/minwith injection volume of 70 μL. Solution concentration was approximately2 mg/mL. Weight average molecular weight (Mw) obtained from GPCmeasurements can be expressed interchangeably, in both, Daltons or g/molunits.

The Nuclear Magnetic Resonance, NMR method identifies and determines thechemical composition of inventive and non-inventive formulations usingproton nuclear magnetic resonance (¹HNMR) spectroscopy. The instrumentused was the 400 MHz (9.4 Tesla) Varian UnityNOVA NMR Spectrometer; anappropriate deuterated solvent, such as Hexafluoroacetonesesquideuterate (HFAD) of at least 99.5% purity D (ETHICON ID #2881, CAS10057-27-9) was used. Sample preparation: In triplicate, 6-10 mg of eachsample was weighted and placed into separate 5 mm NMR tubes. Undernitrogen gas in a glove box, 300+/−10 μL of HFAD was added using 1000 μLsyringe, to each NMR tube and cap. Meanwhile, a solvent blank wasprepared. The samples were then removed from the nitrogen glove bag/boxand NMR tube(s) were placed in a sonic bath, and sonicated until thesample was dissolved, and no evidence of solid polymer existed.Subjecting the samples again under the nitrogen flow, 300+/−10 μLbenzene-d6 was added using a 1000 μL syringe to each NMR tube andcapped. The tubes were shake well to ensure uniform mixing of the HFADand benzene-d6 solvents.

Mechanical properties of the fibers and braids before and afterhydrolysis treatment, such as straight tensile (using uninterrupted,continues straight piece of a fiber or braid) and knot tensile strength(one simple knot introduced in the middle of a fiber or braid) weremeasured by an Instron tester. The Instron model was ID #TJ-41, equippedwith 100-lb load cell LC-147 with pneumatic grips at clamping pressurearound 60 psi. The Instron Gauge speed was one inch per minute with theGauge length of one inch. A 100 lb. load cell was used. For the timezero, steel faces were used on the Instron machine, for all otherhydrolysis times rubber faces were used to avoid slippage. The fiberdiameters were measured using Federal gauge (Products Corp. Providence,R.I.) model #57B-1, identification #W-10761.

In vitro BSR measurements were conducted at physiologically relevant invitro conditions: 7.27 pH phosphate buffered saline solution withmolarity of 0.01M (1×) maintained at 37° C. temperature. Two Haake waterbaths equipped with a ThermoScientific DC10 motor (Model W46, equipmentID: BT-029) were used. The data for BSR evaluations were given in poundsand percentages. At specified time points, the tensile strength ofsamples was tested using an Instron material testing machine. The testparameters were 1 inch gauge length and 1 inch per minute crossheadspeed.

In vivo tissue reaction and total absorption study for the invented EOsterilized braids were conducted at an outside facility following a GLPprotocol and all applicable ISO standards. A total of 68 rats wereimplanted in the gluteal muscles (two sites per side) with one of thetwo test articles on one side and control articles (sterile braids madefrom random 90/10 Gly/Lac copolymer) on the other. A total of 31 ratswere implanted with the size 2/0 sterile braids and 37 rats with thesize 2 sterile braids of the polymers of Ex. 15. For the totalabsorption study, six animals of each of these groups were euthanized at14, 56, 77, and 119 days. At the indicated interval, animals wereeuthanized and implantation sites were collected for histologicalprocessing and microscopic evaluation.

In order to follow conversion of monomers (lactide and glycolide) inreal polymerization time, a FT-NIR spectrometer [Antaris II FourierTransform Near Infrared Spectrometer, supplied by ThermoFischerScientific] equipped with a ¼″ diameter transmission probe and 2-meteroptical cable was used. The measurements were conducted during bothstages of the process. TQ Analyst Software was used to analyze real-timeNIR spectra. The overall scanning (collection) time was set to 64 scans,with 4 cm⁻¹ spectral resolution. Exactly every two minutes the spectrawere collected as a function of reaction time. The area under thecarbonyl peak (the first harmonic overtone of a combination band),located at about 4,800 cm⁻¹ was used to monitor glycolide conversion.For lactide conversion, the first overtone stretching vibration ofmethyl group, located at about 5,700 cm⁻¹ was used for monitoringpurposes. An NIR transmission probe (supplied by Axiom) was placed inthe lower part of the vessel, where a thermocouple measuring the batchtemperature sits.

The following examples are illustrative of the principles and practiceof the present invention, although not limited thereto. Numerousadditional embodiments within the scope and spirit of the invention willbecome apparent to those skilled in the art once having the benefit ofthis disclosure.

Example 1 (Inventive)

Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Difunctional Initiator

Using a 2.5-gallon cone vertical (CV) stainless steel oil jacketedreactor equipped with corotating agitation, 684 grams of glycolide and849 grams of L(−)-lactide were added along with 10.18 ml of diethyleneglycol and 1.19 ml of a 0.33M solution of stannous octoate in toluene.After the initial charge, a vacuum/nitrogen purging cycle with agitationat a rotational speed of 5 RPM (reactor dependent) in an upwarddirection was initiated; the reactor was evacuated to pressures lessthan 250 mTorr followed by the introduction of nitrogen gas. The cyclewas repeated once again to ensure a dry atmosphere. At the end of thefinal nitrogen purge, the pressure was adjusted to be slightly above oneatmosphere. The rotational speed of the agitator was kept at 5 RPM in anupward direction. The vessel was heated by setting the oil temperaturecontroller to 185° C. When the batch temperature reached 110° C.,rotation of the agitator was switched to a forward direction. Thereaction continued for 2.5 hours from the time the batch temperaturereached 180° C.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analysis purposes;selected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 50 mole percent polymerizedlactide and 50 mole percent polymerized glycolide with 2.3 mole percentunreacted monomer. The DSC data revealed that the prepolymer was fullyamorphous with no crystallinity developed even after heat treatment. Theprepolymer exhibited an IV of 0.51 dL/g, and a weight average molecularweight (Mw) of 18,600 Daltons.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 230° C., and 5,468 grams of moltenglycolide monomer was added from a melt tank with an agitator speed of15 RPM in a downward direction for 30 minutes. The agitator speed wasthen reduced to 7 RPM in the downward direction. The reaction proceededfor 1.5 hours from the time of the second glycolide addition,constituting the end of the final reaction period.

At the end of the final reaction period, the agitator speed wasmaintained at 7 RPM in the downward direction, and the polymer wasdischarged from the vessel into suitable containers. Upon cooling, thepolymer was removed from the containers and placed into a freezer set atapproximately −20° C. for a minimum of 12 hours. The polymer was thenremoved from the freezer and placed into a Cumberland granulator fittedwith a sizing screen to reduce the polymer granules to approximately3/16 inches in size. The granules were sieved to remove any “fines” andweighed. The net weight of the ground and sieved polymer was 5.25 kg.The ground polymer was then placed into a 3-cubic foot Patterson-Kelleytumble dryer to help remove residual monomer.

Once charged with the ground polymer, the Patterson-Kelley tumble dryerwas closed, a dryer rotational speed of 4 RPM was initiated, and thepressure was reduced to less than 200 mTorr. These conditions weremaintained with no heat for 18 hours. After the 18-hour period, the oiljacket temperature was set to 140° C. and maintained for 24 hours. Atthe end of the 24-hour heating period, the batch was allowed to cool fora period of 2 hours while maintaining rotation and vacuum. Aftercooling, the polymer was discharged from the dryer by pressurizing thevessel with nitrogen, opening the discharge valve, and allowing thepolymer granules to descend into waiting vessels for long-term storage.

The long-term storage vessels were air tight and outfitted with valvesallowing for evacuation so that the resin was stored under vacuum. Thedried resin exhibited an IV of 1.35 dL/g, and a Mw of 67,800 Daltons.NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 0.4 mole percent. The glass transitiontemperature (T_(g)) of the dried resin was 52° C., the melting point(Tm) was 215° C., and the heat of fusion (ΔH_(m)), was 70.9 J/g asdetermined by DSC using the first heat scan. Wide Angle X-RayDiffraction (WAXD) data on the dried sample revealed 42% crystallinity.

Example 2 (Non-Inventive/Comparative)

Synthesis of a Segmented A-B Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Monofunctional Initiator

In this Example, dodecanol as a monofunctional initiator was used (as inthe prior art U.S. Pat. No. 6,007,565) instead of diethylene glycol(difunctional initiator).

Using a 2.5-gallon cone vertical (CV) stainless steel oil jacketedreactor equipped with corotating agitation, 684 grams of glycolide and849 grams of L(−)-lactide were added along with 24.0 ml of dodecanol(DD) and 1.19 ml of a 0.33M solution of stannous octoate in toluene.After the initial charge, a vacuum/nitrogen purging cycle with agitationat a rotational speed of 5 RPM in an upward direction was initiated. Thereactor was evacuated to pressures less than 250 mTorr followed by theintroduction of nitrogen gas. The cycle was repeated once again toensure a dry atmosphere. At the end of the final nitrogen purge, thepressure was adjusted to be slightly above one atmosphere. Therotational speed of the agitator was kept at 5 RPM in an upwarddirection. The vessel was heated by setting the oil controller at 185°C. When the batch temperature reached 110° C., rotation of the agitatorwas switched to a downward direction. The reaction continued for 2.5hours from the time the batch temperature reached 180° C., constitutingthe end of the first stage polymerization.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analysis purposes andselected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 50 mole percent polymerizedlactide and 50 mole percent polymerized glycolide with 2.1 mole percentof unreacted monomer. The DSC data revealed that the prepolymer wasfully amorphous with no crystallinity developed even after heattreatment. The prepolymer (B-segment) exhibited an inherent viscosity of0.61 dL/g and a Mw of 23,500 Daltons.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 230° C. and 5,468 grams of moltenglycolide monomer was added from a melt tank with the agitator speed of15 RPM in an upward direction for 30 minutes. The agitator speed wasthen reduced to 7 RPM in the downward direction. The reaction proceededfor 1.5 hours from the time of the second glycolide addition,constituting the end of the final reaction period.

At the end of the final reaction period, the agitator speed wasmaintained at 7 RPM in the downward direction, and the polymer wasdischarged from the vessel into suitable containers. Upon cooling, thepolymer was removed from the containers and placed into a freezer set atapproximately −20° C. for a minimum of 12 hours. The polymer was thenremoved from the freezer and placed into a Cumberland granulator fittedwith a sizing screen to reduce the polymer granules to approximately3/16 inches in size. The granules were sieved to remove any “fines” andweighed. The net weight of the ground and sieved polymer was 4.72 kg.The ground polymer was then placed into a 3-cubic foot Patterson-Kelleytumble dryer to help remove residual monomer.

Once charged with the ground polymer, the Patterson-Kelley tumble dryerwas closed, a dryer rotational speed of 3 RPM was initiated, and thepressure was reduced to less than 200 mTorr. These conditions weremaintained with no heat for 18 hours. After the 18-hour period, the oiljacket temperature was set to 140° C. and maintained for 24 hours. Atthe end of the 24-hour heating period, the batch was allowed to cool fora period of 2 hours while maintaining rotation and vacuum. Aftercooling, the polymer was discharged from the dryer by pressurizing thevessel with nitrogen, opening the discharge valve, and allowing thepolymer granules to descend into waiting vessels for long term storage.

The long-term storage vessels were air tight and outfitted with valvesallowing for evacuation so that the resin was stored under vacuum. Thedried resin exhibited an inherent viscosity of 1.35 dL/g, and a Mw of66,200 Daltons. NMR analysis confirmed that the resin contained 90 molepercent polymerized glycolide and 10 mole percent polymerizedL(−)-lactide, with a residual monomer content of 1.9 mole percent. TheTg, of the dried resin was 47° C., the Tm was 218° C., and the ΔHm was74.7 J/g as determined by the DSC first heat scan.

Impact of Initiator Type on Resin Properties

Since DEG is used in Example 1, the resulting copolymer has an A-B-Achain sequence as presented before. If a monofunctional initiator isused, such as DD, the chain sequence would be of the form A-B. Toevaluate the impact of this structural change on suture performance, aresin was made as described in Example 2 in which DD was used as theinitiator instead of DEG, both having an overall target composition of90/10 glycolide/lactide and a target B-segment composition of 50/50glycolide/lactide.

A comparison of the copolymer properties between Example 1 and Example 2is summarized in the Table 1.

TABLE 1 Polymer Properties of DEG and DD Initiated Polymers from Example1 and Example 2, Respectively Example 1 Example 2 (DEG-Initiated)(DD-Initiated) Prepolymer Mw (g/mol) 18,607 23,500 (B-Segment) IV (dL/g)0.51 0.61 Unreacted Monomer 2.3 2.1 (mol %) Dried Mw (g/mol) 67,80066,200 Polymer IV (dL/g) 1.35 1.35 Polymerized Glycolide 89.9 88.3 (mol%) Unreacted Glycolide 0.3 1.6 Monomer (mol %) Polymerized Lactide 9.79.8 (mol %) Unreacted Lactide 0.1 0.3 Monomer (mol %) Tm (° C.) 215 218Tg (° C.) 52 47 AC_(L)SL 2.4 2.7

The two polymers were similar in terms of their final Mw, IV, prepolymercomposition, and final polymer composition. However, the prepolymer IVof the DD batch was higher than that of the DEG batch, which is alsosupported by the higher Mw results. However, the monomer to initiatorratio (IR) was 614:1 and 457:1 for Example 1 and Example 2,respectively, resulting in practically identical final copolymer IV andMw.

The Tm was also higher for the DD batch. This is because the polymerizedglycolide block (A-segment) for the A-B type polymer (DD initiated) willbe almost twice as long as the polymerized glycolide end segments in theA-B-A type polymer (DEG initiated). Since the glycolide A-segment ismuch longer for the DD-initiated A-B type polymer, the polymer systemwill tend to behave closer to a polyglycolide homopolymer, which has amelting point of about 224° C.

Both of these copolymers were extruded into 56 denier yarn and braidedinto size 2/0 suture. The extrusion and braiding details are given inExample 13.

Examples 3-12 (Inventive and Non-Inventive)

Synthesis of Segmented A-B-A Block Copolymers ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition Having Different B-Segment Molar Compositions, allUsing Difunctional Initiator

The synthesis procedure as described in Example 1 was repeated in a2.5-Gallon cone vertical (CV) reactor using difunctional initiator(DEG), at an initiator ratio (moles of monomer:moles of initiator) of550:1, but varying the B-segment (prepolymer) monomer composition, whilekeeping the final molar composition of 90/10 glycolide/lactide constant.The same catalyst (stannous octoate) and catalyst ratio (moles ofmonomer:moles of catalyst) of 150,000:1 was used for all the trials.Table 2 lists the different B-segment target molar compositions of thevarious A-B-A block copolymers made by this approach.

TABLE 2 List of B-Segment Molar Compositions of the A- B-A BlockCopolymers Produced in Examples 3-12 B-Segment Monomer MeasuredB-Segment Feed Ratio in Polymer Composition Example Mole Percent in MolePercent* Number (glycolide/lactide) (glycolide/lactide) Example 3 80/2079.7/18.7 Example 4 70/30 69.7/28.8 Example 5 60/40 59.7/38.5 Example 650/50 49.8/48.0 Example 7 40/60 39.8/56.2 Example 8 30/70 30.2/66.3Example 9 20/80 20.6/75.5 Example 10 15/85 15.7/79.3 Example 11 10/9011.4/83.9 Example 12  5/95  6.0/84.9 *Does not include unreactedmonomer.Overall Copolymer Composition Summary:

The A-B-A copolymers at the end of the polymerization (dischargedresin), and after the drying step were characterized. The NMR resultsdemonstrated that the overall copolymer compositions at the dischargeand after drying were consistent across all runs as shown in Table 3.

TABLE 3 Average Overall Polymer Composition of the Discharged Polymerand of the Dried Polymer from Examples 3-12 by NMR Average Standard(mole %) Deviation Discharged Polymer Polymerized Glycolide 89.3 0.4Unreacted Glycolide 1.1 0.4 Monomer Polymerized Lactide 9.4 0.4Unreacted Lactide 0.2 0.0 Monomer Dried Polymer Polymerized Glycolide89.8 0.6 Unreacted Glycolide 0.6 0.4 Monomer Polymerized Lactide 9.5 0.3Unreacted Lactide 0.2 0.1 MonomerMw and IV Summary:

The copolymer resins produced from Examples 3-12 were analyzed for Mwand IV. The Mw ranged from 57,000 to 74,200 g/mol at reactor discharge,and from 54,200 to 72,500 g/mol after drying. This aligned with thespread of IV generated, which ranged from 1.22 to 1.53 dL/g for thedried copolymers. FIG. 1 and FIG. 2 summarize the Mw and IV results forthese polymer samples respectively.

Sequence Distribution Summary:

In order to characterize the sequence distribution of the resultingcopolymers, the Average Chain Sequence Length (ACSL) of the lactoylmoiety {—OCH(CH₃)C═O-} was assessed using NMR. It's known thatpolymerized lactide monomer is composed of two lactoyls in series thatare relatively stable. Therefore, the lactoyl ACSL (ACLSL) for a random90G/10L copolymer is expected to be close to 2. As conventionallycalculated by the Harwood run number [ACSL=1+x/y], the ACLSL ispredicted to equal 1.11 for the random copolymer [1+10/90=1.11].However, because the polymerized lactide repeat unit does not typicallysplit, transesterification of adjoining lactoyls are usually notobserved. Therefore, the ACLSL of a fully randomized 90/10glycolide/lactide copolymer, where the lactoyl repeat unit is(—OCH(CH₃)C═O—)_(n), would be 2.11 [2+x/y=2.11].

For the copolymers of Example 1, and Examples 3-12, since all thelactide is contained in the center segment of the A-B-A polymer chain(B-segment), the ACLSL of the A-B-A polymer is expected to increase asthe lactide content in the B-segment composition is increased. A plot ofthe ACLSL results of the A-B-A polymer are shown in FIG. 3 and arealigned to the previously stated expectation, in which the ACLSLincreased from 2 when as the percent lactide in the B-segment isincreased.

Example 13

Extrusion and Braiding of the Copolymers Described in Examples 1-12

Extrusion and Orientation Apparatus and Conditions

The copolymers described in Examples 1-12 were extruded into multiplefilament strands through a 1-inch conventional vertical extruder. Theextruded multifilament strands were collected on a take-up winder andthen drawn on a conventional drawing stand. Typical processingconditions are provided in Table 4.

TABLE 4 Extrusion and Orientation Conditions Extrusion Components Rangeof Variables Extruder Feed Zone Temp. (° C.) 165-205 Extruder TransitionZone Temp. (° C.) 185-225 Extruder Metering Zone Temp. (° C.) 190-245Extruder Barrel Pressure (psi) 1200 (±300)  Metering Pump Temp. (° C.)185-255 Pump Outlet Pressure (psi) 1500-5000 Extrusion Block Temp. (°C.) 185-255 Spinneret Temp. (° C.) 205-265 Heated Sleeve/Chimney Temp (°C.) 235-310 Distance from Die to 1^(st) Take-Up Godet About 17 feetTake-up Winder Speed (fpm) 1732 (+/−20) Orientation Conditions OperatingRange Orientation Roll Temperature (° C.) 75-95  Drawing RollTemperature (° C.) 95-135 Let-off Roll Temperature (° C.) AmbientOrientation Roll Speed (fpm) 200 (+/−7) Drawing Roll Speed (fpm)  998(+/−10) Let-off Roll Speed (fpm) 1000 (+/−10) Total Draw Ratio about 5.0Drawn Denier Per Filament (DPF) about 2.0 Total Drawn Yarn Denier 10-100

Note that the drawn fiber size is preferably kept constant at about 2.0denier per filament (dpf) using a fixed total draw ratio of around 5.0.Based on the suture size and total yarn denier needed, the number ofspinneret holes, metering pump size and speed may be varied. Forexample, to make size 2-0 suture with 56-denier yarn, a spinneret of 28holes would be used with a ½ size pump having a throughput of about 0.30cc/rev at a speed of about 41 rpm. Depending on the polymer molecularweight, IV or melt index, the temperatures of the extrusion and/ororientation may be varied or optimized to achieve desirable optimumfiber properties within the ranges recommended in Table 4 above.

Braiding Conditions

To produce braided suture material, yarns were first bobbin wound andbraided using a 16-carrier/3 core construction on a New England Buttbraider. After braiding, the material was skeined and solvent scoured inethyl acetate to remove lubricant finishes and foreign materialsaccumulated during upstream manufacturing steps. Using dedicatedequipment, all skeins were skein-scoured in an opened-top for 15minutes, and drip-dried. After scouring, the skeins were then re-spooledfor subsequent hot stretching. During the hot stretching process, thesuture material was drawn on heated rolls in order to mechanically alignthe core and sheath yarns of the braid. For the size 2-0 sutureproduced, a draw ratio of 14% was used. After hot stretching, the suturematerial was rack annealed in an inert gas annealing oven for 6 hours ata temperature of 124° C.

Example 14

Physical Properties of the Braids Produced and Described in Example 13

Impact of Initiator Type on Braid Physical Properties, Including BSR

The copolymers of Examples 1 and 2 were extruded into 56d yarn andbraided into size 2/0 suture as described in Example 13. The results aresummarized in Table 5.

TABLE 5 Tensile Strength and BSR Results of 2-0 Braids Made from DEG andDD Initiated Copolymers of Examples 1 and 2 Polymer Knot StraightExample Initiator Tensile Tensile 35 Day 42 Day No. Type (lbs.) (lbs.) %BSR % BSR 1 DEG 9.83 17.6 58.3 26.7 2 DD 9.52 17.9 32.0 9.4

Although the initial knot tensile and straight tensile strengths aresimilar between the braids constructed from DEG and DD initiatedpolymers of Examples 1 and 2, the most unexpected and surprising resultobserved was the significant impact of initiator type on BSRperformance. The braid constructed from DD-initiated polymer of Example2 exhibited significantly shorter BSR performance than the braidconstructed from the DEG-initiated polymer of Example 1. This clearlydemonstrated the critical importance of using a difunctional initiatorto produce A-B-A types of 90/10 glycolide/lactide copolymers for use insuture systems that require extended BSR properties.

B-Segment Compositional Assessment on Braid Physical Properties

To explore the impact of B-segment composition on suture performance, aseries of A-B-A type copolymers were produced with different B-segmentcompositions, as described in Examples 3-12. The explored B-segmentcompositions ranged from 20 mole % to 95 mole % lactide. Theirextrusion, braiding and post-processing steps were presented in Example13. Table 6 summarizes the various A-B-A copolymers that were producedalong with their resulting size 2-0 suture knot tensile, straighttensile, and BSR results. In addition, FIG. 4 and FIG. 5 that providethe BSR performance and straight tensile strength of the suture versusB-segment composition, respectively.

TABLE 6 Size 2-0 Suture Performance Made from the A-B-A Copolymers withVarious B-Segment Compositions of Examples 3-12 B-Segment Composition(Glycolide/ Knot Straight Example Lactide) Tensile Tensile 35 Day 42 DayNo. (Mole %) (lbs.) (lbs.) % BSR % BSR 12  5/95 9.78 17.09 29.5 4.7 1110/90 9.78 16.57 31.5 4.9 10 15/85 9.68 16.27 32.7 0.0 9 20/80 10.1317.14 43.5 13.2 8 30/70 9.65 17.61 48.4 18.9 7 40/60 9.65 17.34 51.626.8 6 50/50 9.83 17.57 58.3 26.7 5 60/40 9.89 16.52 50.5 20.6 4 70/309.62 16.05 35.1 8.0 3 80/20 9.93 19.02 24.4 6.3

Surprisingly, the suture braid constructed from the A-B-A copolymer thathad a B-segment molar composition of 50/50 glycolide/lactide (Example 6)produced the best 35-day BSR performance. Also, the samples producedfrom B-segment molar compositions of 50/50 (Example 6) and 40/60glycolide/lactide (Example 7) exhibited the best 42-day BSR performance,both yielding % BSR of around 27%. This is a very important discovery,paving the way for the optimal chemical architecture of a B-segmentcomposition of 50-60 mole percent of lactide in the overall A-B-Acopolymer. The initial straight and knot tensile strengths of thesutures of these examples were not significantly impacted by changingthe composition of the B-segment. Therefore, a target B-segment molarcomposition of 50/50 glycolide/lactide was identified as an optimal forthe A-B-A type copolymers having an overall molar composition of 90/10glycolide/lactide, as they yield materials that could be very useful forsuture applications requiring extended BSR.

Example 15 (Inventive)

Large-Scale Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Difunctional Initiator

This example describes the inventive synthesis of a segmented A-B-Ablock copolymer with an overall target molar composition of 90/10glycolide/lactide and a target B-segment molar composition of 50/50glycolide/lactide, in the larger-scale 15-gallon Benco-style reactorwith critical fast agitation at the start of the second stage, lowcatalyst ratio of 150k:1, initiator ratio of 750:1, and a pelletizationprocess for the discharge. Throughout the polymerization, monomerconversion was monitored in real-time by remote FT-NIR spectroscopy(Antaris II, Thermo) using a ¼″ NIR transmission probe (supplied byAxiom).

Using a large-scale 15-gallon stainless steel Benco reactor equippedwith an oil jacket and agitation, 6,347 grams of glycolide and 7,881grams of L(−)-lactide were added along with 77.4 grams of difunctionalinitiator (DEG), 11.05 ml of a 0.33M solution of stannous octoate intoluene, and 130 grams of D&C Violet Number 2 dye. After the initialcharge, a vacuum/nitrogen purging cycle with agitation at a rotationalspeed of 10 RPM in an upward direction for 20 minutes was initiated. Thereactor was evacuated to pressures less than 200 mTorr followed by theintroduction of nitrogen gas. The cycle was repeated once again toensure a dry atmosphere. At the end of the final nitrogen purge, thepressure was adjusted to be slightly above one atmosphere and the oiltemperature controller was set to 185° C., while the rotational speed ofthe agitator was maintained at 10 RPM in an upward direction. After 45minutes of heating, the rotation of the agitator was switched to adownward direction. The reaction continued for about 3 hours from thetime the agitator rotation was switched to forward direction,constituting the end of the first polymerization stage.

After the completion of the first stage portion of the polymerization, avery small amount of the prepolymer resin (B-segment) was discharged foranalysis purposes and characterization was performed. The chemicalcomposition of the prepolymer, as determined by NMR, was 50 mole percentpolymerized glycolide and 50 mole percent polymerized lactide with about2 mole percent of unreacted monomer remaining, consisting mostly oflactide. The DSC data revealed that the prepolymer was fully amorphouswith no crystallinity developed even after heat treatment. Theprepolymer exhibited an IV of 0.60 dL/g, and a Mw of 24,700 Daltons.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 215° C. and the agitator was set to20 RPM in an upward direction, upon which an additional 50,773 grams ofmolten glycolide monomer was added from a melt tank. After 60 minutesfrom the second glycolide charge, the agitator speed was then reduced to15 RPM in the forward direction and the oil temperature setting wasreduced to 207° C. for the reminder of the run. The reaction proceededfor a total of 165 minutes from when the second glycolide addition wasperformed, constituting the end of the final stage reaction.

At the end of the final reaction period, the agitator speed was reducedto 4 RPM in the downward direction, and the polymer was discharged usingthe Gala underwater pelletizing apparatus. The die hole size was 0.093″with 4 holes opened. The die temperature was kept between 247 and 275°C. The pelletizer material output was about 118 kg/hr, yielding a netweight of 54.2 kg. Upon cooling, the pellets were placed in the freezerfor storage until drying. The pellets were then placed into a 3-cubicfoot Patterson-Kelley tumble dryer to help remove residual monomer. Thedrying procedure was carried out exactly as described in Examples 1 and2.

The dried pellets exhibited an IV of 1.39 dL/g and a Mw of 71,200Daltons. NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 0.7 mole percent. The Tg of the driedresin was 50° C., the T_(m) was 216° C., and the ΔH_(m) was 53.2 J/g asdetermined by DSC using the first heat scan. Wide Angle X-RayDiffraction (WAXD) data on the dried sample revealed 38% crystallinity.

Example 16 (Inventive)

Large-Scale Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Difunctional Initiator, and Dual CatalystAddition

This example describes the inventive synthesis of a segmented A-B-Ablock copolymer with an overall target molar composition of 90/10glycolide/lactide and a target B-segment molar composition of 50/50glycolide/lactide, in a 15-gallon reactor with an extra low catalystlevel (catalyst ratio of 200k:1), using a dual catalyst addition methodin which a portion of catalyst is added at the start of first stagereaction, and a second portion of catalyst is added in early stages ofthe second stage polymerization. The use of this dual catalyst additionmethod allows for an ultra-low catalyst concentration to be employed.Throughout the polymerization, monomer conversion was monitored inreal-time by remote FT-NIR spectroscopy (Antaris II, Thermo) using a ¼″NIR transmission probe (supplied by Axiom).

Using a large-scale 15-gallon stainless steel oil jacketed Benco reactorequipped with agitation, 4,882 grams of glycolide and 6,062 grams ofL(−)-lactide were added along with 59.5 grams of difunctional initiator(DEG), 2.12 ml of a 0.33M solution of stannous octoate in toluene, and100 grams (0.2 weight percent) of D&C Violet Number 2 dye was added.After the initial charge, a vacuum/nitrogen purging cycle with agitationat a rotational speed of 10 RPM in an upward direction for 20 minuteswas initiated. The reactor was evacuated to pressures less than 200mTorr followed by the introduction of nitrogen gas. The cycle wasrepeated once again to ensure a dry atmosphere. At the end of the finalnitrogen purge, the pressure was adjusted to be slightly above oneatmosphere. The rotational speed of the agitator was kept at 10 RPM inan upward direction and the vessel was heated by setting the oilcontroller at 185° C. After 30 minutes the rotation of the agitator wasswitched to a forward direction. The first stage reaction continued forabout 5 hours, based on NIR measurements, to account for slower monomerconversion resulting from lower catalyst level in the first stage.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analysis purposes andselected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 50 mole percent polymerizedglycolide and 50 mole percent polymerized lactide with about 2 molepercent of unreacted monomer, mostly lactide. The DSC data revealed thatthe prepolymer was fully amorphous with no crystallinity developed evenafter heat treatment. The prepolymer (B-segment) exhibited an inherentviscosity of 0.59 dL/g and a Mw of 24,300 Daltons. Wide Angle X-RayDiffraction (WAXD) data on the dried sample revealed 41% crystallinity.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 216° C. and the agitator speed anddirection was set to 18 RPM upward, after which 38,656 grams of moltenglycolide monomer was added from a melt tank. After 10 minutes from thesecond glycolide charge, the agitator direction was set to 18 RPMforward. After 30 minutes from the second glycolide charge, the secondcatalyst addition of 4.25 ml was conducted to achieve an overallcatalyst ratio of 200k:1. To ensure all of the catalyst in this secondcatalyst addition was captured, the 4.25 ml of catalyst was mixed withof 400 grams of glycolide in powder form before adding to the reactor.When the catalyst addition was complete, the oil temperature controllerwas set to 207° C. and the agitator RPM was reduced to 7.5 for thereminder of the run. The reaction proceeded for 165 minutes from thesecond glycolide charge prior to the discharge, constituting the end ofthe final reaction period.

At the end of the final reaction period, the agitator speed wasmaintained at 7.5 RPM in the downward direction, and the polymer wasdischarged from the vessel into suitable containers. Upon cooling, thepolymer was placed into a freezer set at approximately −20° C. for aminimum of 12 hours. The polymer was then removed from the freezer andplaced into a Cumberland granulator fitted with a sizing screen toreduce the polymer granules to approximately 3/16 inches in size. Thegranules were sieved to remove any “fines” and weighed. The net weightof the ground and sieved polymer was 42.4 kg and was then placed into a3-cubic foot Patterson-Kelley tumble dryer to remove any residualmonomer. The drying procedure was carried out exactly as described inExamples 1 and 2.

The dried pellets exhibited an IV of 1.46 dL/g and a Mw of 76,500Daltons. NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 0.6 mole percent. The Tg of the driedresin was 46° C., the T_(m) was 216° C., and the ΔH_(m) was 67.8 J/g asdetermined by DSC using the first heat scan.

As mentioned previously, a FT-NIR spectrometer equipped with a ¼″diameter transmission probe and 2-meter optical cable was used to followglycolide and lactide conversion in real polymerization time during bothstages of the reaction. In FIG. 6A, the area under the glycolide andlactide peaks are plotted against the reaction time in the firstpolymerization stage for the batch made in this Example. In FIG. 6B, thearea under the monomer peaks are converted into percentages and theconversion progress is graphically illustrated as a function of reactiontime. An assumption was made, based on real-time FT-NIR monitoring, wasthat monomer conversion was sufficiently complete at the end of thefirst stage. Based on NMR results on the inventive prepolymers,glycolide generally converted to almost 100%, but about 1.5-2.0 molepercent of lactide monomer remained after the first stage. Thisunreacted lactide is available for polymerization in the second stage ofthe reaction, incorporating into the glycolide A-segments. Therefore, tomaintain A-segments that are substantially comprised of glycolide, it isimportant to achieve as much lactide monomer conversion in the firststage as possible to minimize the available lactide in the second stage.

As FIGS. 6A and 6B indicate, the glycolide conversion in the first stagewas very fast for Example 16, and after about 40-50 minutes appeared toreach the completion. On the other hand, the lactide polymerization ratewas notably slower, especially in the later prepolymer stages, and tooklonger time to convert down to about 2 mole % of its original value.

Example 17 (Inventive)

Large-Scale Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Difunctional Initiator, and Slow Agitation inthe Second Stage

This example describes the inventive synthesis of a segmented A-B-Ablock copolymer with an overall target molar composition of 90/10glycolide/lactide and a target B-segment molar composition of 50/50glycolide/lactide in a large-scale 15-gallon Benco reactor with acatalyst ratio of 150k:1, with all catalyst added in the first stage asin Example 15, but with slower agitation at the beginning of thecritical second stage reaction period. It will be shown that this methodwas not optimal in producing a resin that would result in sutures withlonger BSR performance. Throughout the polymerization, monomerconversion was monitored in real-time by remote FT-NIR spectroscopy(Antaris II, Thermo) using a ¼″ NIR transmission probe (supplied byAxiom).

Using a large-scale 15-gallon stainless steel oil-jacketed Benco reactorequipped with agitation, 4,882 grams of glycolide and 6,062 grams ofL(−)-lactide were added along with 59.5 grams of difunctional initiator(DEG), 8.50 ml of a 0.33M solution of stannous octoate in toluene, and100 grams of D&C Violet Number 2 dye. After the initial charge, avacuum/nitrogen purging cycle with agitation of 10 RPM in an upwarddirection for 20 minutes was initiated. The reactor was evacuated topressures less than 300 mTorr followed by the introduction of nitrogengas. The cycle was repeated once again to ensure a dry atmosphere. Atthe end of the final nitrogen purge, the pressure was adjusted to beslightly above one atmosphere, while maintaining an agitator speed of 10RPM in an upward direction. The vessel was heated by setting the oilcontroller at 185° C. After 30 minutes from initiating heat, theagitator was switched to a forward direction. The reaction continued for3.5 hours from the time the oil temperature was set at 185° C.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analytical purposes andselected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 50 mole percent polymerizedglycolide and 50 mole percent polymerized lactide with about 2 molepercent of residual unreacted monomer, mostly lactide. The DSC datarevealed that the prepolymer was fully amorphous with no crystallinitydeveloped even after heat treatment. The prepolymer (B-segment)exhibited an IV of 0.62 dL/g and a Mw of 25,900 Daltons.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 216° C. while setting the agitatorspeed to 18 RPM upward, after which an additional 39,056 grams of moltenglycolide monomer was added from a melt tank. After 10 minutes from thesecond glycolide addition, the agitator speed was changed to forwardrotation. After 30 minutes from the second glycolide charge, the oiltemperature was set to 207° C. After 60 minutes from the secondglycolide charge, the agitation speed was reduced to 7.5 RPM for thereminder of the run. The reaction proceeded about 165 minutes from thesecond glycolide charge prior to the discharge, constituting the end ofthe final reaction period.

At the end of the final reaction period, the agitator speed wasmaintained at 7.5 RPM in the downward direction, and the polymer wasdischarged from the vessel into suitable containers. Upon cooling, thepolymer was removed from the containers and placed into a freezer set atapproximately −20° C. for storage for a minimum of 12 hours. The polymerwas then removed from the freezer and placed into a Cumberlandgranulator fitted with a sizing screen to reduce the polymer granules toapproximately 3/16 inches in size. The granules were sieved to removeany “fines” and weighed. The net weight of the ground and sieved polymerwas 35.3 kg, and this ground polymer was then placed into a 3-cubic footPatterson-Kelley tumble dryer to remove residual monomer. The dryingprocedure was carried out exactly as described in Examples 1 and 2.

The dried pellets exhibited an IV of 1.39 dL/g and a Mw of 72,300Daltons. NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 1.8 mole percent. The Tg of the driedresin was 47° C., the T_(m) was 215° C., and the ΔH_(m) was 63.1 J/g, asdetermined by DSC using the first heat scan.

Inadequate mixing efficiency for this batch was identified inreal-processing time by the remote FT-NIR spectroscopy. In FIG. 7 , thesecond stage glycolide conversion for the Example 17 batch was given asa function of the second stage polymerization time. Corresponding dataon two previous inventive batches, Examples 15 and 16, are also includedfor a comparison.

As FIG. 7 indicates, it took a much longer time for glycolide monomer toconvert for the Example 17 batch than expected based upon resultsobtained on previous batches (Examples 15 & 16). This is due to thedifficulty of mixing the relatively low viscosity molten glycolidemonomer from the melt tank with the relatively high viscosityprepolymer. Inadequate mixing would slow down the copolymerization ratesand affect the physical properties of the resin. Several critical stepswere implemented in this study that helped in solving this problem.These are: a) faster agitation speed; b) extending the mixing time, orthe time in which a faster agitation speed and higher reactortemperature is applied; c) increased prepolymer batch temperature priorto the second glycolide addition; and/or, d) using the dual catalystaddition as successfully demonstrated in Example 16.

The dried resins of Examples 15-17 were extruded and braided into 2-0size suture according to the procedures described in Example 13. Theannealed braids were submitted for in vitro BSR testing, and the resultsare presented in Table 7.

TABLE 7 42-Day BSR Results for 2-0 Braids Made from Examples 15-17Standard Example 42 Day Deviation Number % BSR (%) 15 42.6 0.1 16 40.24.3 17 24.6 6.5

It is evident from the data presented in Table 7 that inadequate mixingduring the early stages of the second polymerization step of Example 17negatively affected the 42-day BSR performance. On the other hand, thebraids made from the polymer of Example 15 which used optimized mixingconditions, and the braids made from the polymer of Example 16 whichused dual catalyst addition and ultra-low total catalyst level,generated significantly better 42-day BSR results. It should be notedthat the 42-day BSR of 24.6% of Example 17 is still well above the42-day BSR values achieved for the sutures made from the A-B typecopolymers of Examples 19 and 20, which both yielded 42-day BSR valuesof <1%.

Example 18 (Inventive)

Large-Scale Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using High Catalyst Level

The resin for this example was produced in the same manner as describedin Example 15, except that a higher catalyst level was used. Thecatalyst ratio, as defined as “moles monomer:moles of catalyst” wasdecreased from 150k:1 to 120k:1. Note that since catalyst level isdefined as “moles of monomer:moles of catalyst”, a lower catalyst ratiocorresponds to a higher catalyst level. For example, a catalyst ratio of150k:1 is equivalent to a catalyst level of 6.7 PPM, while a catalystratio of 120k:1 is equivalent to a catalyst level of 8.3 PPM.

The dried pellets of Example 18 exhibited an IV of 1.32 dL/g and aM_(w), of 67,800 Daltons. NMR analysis confirmed that the resincontained 90 mole percent polymerized glycolide and 10 mole percentpolymerized L(−)-lactide, with a residual monomer content of 1.7 molepercent. The Tg of the dried resin was 48° C., the T_(m) was 214° C.,and the ΔH_(m) was 58.3 J/g as determined by DSC using the first heatscan.

Effect of Catalyst Level on BSR Properties

This example teaches that higher concentration of catalyst cannegatively affect the properties of the final product. Higher catalystconcentration may lead to additional thermal degradation during thepolymerization process and during downstream processing steps such asextrusion. On the other hand, lower levels of catalyst can lead tobetter thermal stability during polymerization and downstreamprocessing, thus limiting the transesterifications and loss in molecularweight. The dried pellets from Example 18 were extruded and braided intotwo suture sizes using procedures described in Example 13. The annealedbraids were submitted for in vitro BSR evaluation. In Table 8, theproperties of the braid constructed from the copolymers of Example 18and Example 15 are shown for a direct comparison.

TABLE 8 The Effect of Catalyst Level on Braid Properties of BraidsConstructed from the Copolymers Described in Examples 15 and 18 Catalystratio Knot Straight 42 Day Example (moles monomer: USP Tensile TensileBSR 42 Day Number moles catalyst) Size (lbs.) (lbs.) (lbs.) % BSR 15150k:1 1 19.4 36.5 14.2 40.7 2-0 10.9 19.7 8.4 42.5 18 120k:1 1 17.335.0 7.9 23.7 2-0 9.3 17.5 4.3 24.0

As indicated in Table 8, initial tensile properties (straight and knottensile) were slightly higher for the braids made from Example 15 (lowercatalyst), but the in vitro BSR results were significantly better, bothin pounds remaining and in percent BSR. The lower BSR results for thebraids made from Example 18 could be the result of additionaltransesterification reactions, enabled by the increased catalyst level.This is a very similar case to Example 21, presented later in the text,where even higher catalyst level was used. As shown before, thisresulted in randomization of the blocky structure and reduction in BSRperformance. When comparing braids produced from the polymers of Example15 and Example 18, the effect of catalyst level on BSR is clearlynoticeable.

Example 19 (Non-Inventive and Comparative to Prior Art)

Synthesis of a Segmented A-B Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 55/45Glycolide/Lactide, Using Monofunctional Initiator

This example of a A-B block copolymer of poly(glycolide-co-L(−)-lactide)at an overall 90/10 glycolide/lactide molar composition [B-segmenttarget molar composition of 55/45 glycolide/lactide] was made based onthe teachings of U.S. Pat. No. 6,007,565 (Roby et al.) to demonstratethe criticality of using the procedures of the present invention for thedesired long-BSR suture applications.

Using a 2.5-gallon stainless steel oil jacketed CV reactor equipped withcorotating agitation, 980 grams of glycolide and 980 grams ofL(−)-lactide were added along with 4.72 ml of monofunctional initiator(DD) and 3.97 ml of a 0.33M solution of stannous octoate in toluene. Thedye, D&C Violet Number 2 (14 grams), was added as well. After theinitial charge, a vacuum/nitrogen purging cycle with agitation at arotational speed of 5 RPM in an upward direction was initiated. Thereactor was evacuated to pressures less than 150 mTorr followed by theintroduction of nitrogen gas. The cycle was repeated once again toensure a dry atmosphere. At the end of the final nitrogen purge, thepressure was adjusted to be slightly above one atmosphere. Therotational speed of the agitator was kept at 5 RPM in an upwarddirection. The vessel was heated by setting the oil controller at 170°C. When the oil temperature reached 170° C., rotation of the agitatorwas switched to a downward direction. The reaction continued for 5.0hours from the time the oil temperature reached 170° C.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analytical purposes andselected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 55 mole percent polymerizedglycolide and 45 mole percent polymerized lactide with about 3 molepercent of residual unreacted monomer, mostly lactide. The DSC datarevealed that the prepolymer was fully amorphous with no crystallinitydeveloped even after heat treatment. The prepolymer (B-segment)exhibited an IV of 1.75 dL/g and a M_(w) of 105,600 Daltons.

In the second stage of the polymerization 420 grams of glycolide wasadded to the reactor, and then the heating oil controller set point wasraised to 220° C. When the oil temperature in the reactor reached 210°C., an additional 4,620 grams of molten glycolide monomer was added froma melt tank with the agitator speed of 25 RPM in an upward direction for15 minutes. After 15 minutes, the agitator speed was then reduced to 20RPM in the downward direction, and after another 15 minutes the agitatorspeed was further reduced to 15 RPM in a forward direction. Afteranother 30 minutes the agitation was reduced to 7.5 RPM in a forwarddirection for the reminder of the run. The reaction proceeded 165minutes from the last glycolide charge prior to the discharge,constituting the end of the final reaction period.

At the end of the final reaction period, the agitator speed was reducedto 4 RPM in the downward direction, and the polymer was discharged fromthe vessel into suitable containers. Upon cooling, the polymer wasplaced into a freezer set at approximately −20° C. for storage for aminimum of 12 hours. The polymer was then removed from the freezer andplaced into a Cumberland granulator fitted with a sizing screen toreduce the polymer granules to approximately 3/16 inches in size. Thegranules were sieved to remove any “fines” and weighed. The net weightof the ground and sieved polymer was 4.80 kg; the ground polymer wasthen placed into a 3-cubic foot Patterson-Kelley tumble dryer to removeany residual monomer. The drying procedure was carried out exactly asdescribed in Examples 1 and 2.

The dried resin exhibited an IV of 1.41 dL/g and a Mw of 76,100 Daltons.NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 0.3 mole percent. The Tg of the driedresin was 46° C., the T_(m) was 219° C., and the ΔH_(m) was 63.6 J/g asdetermined by DSC using the first heat scan.

Example 20 (Non-Inventive and Comparative Example to Prior Art)

Synthesis of a Segmented A-B Block CopolymerPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 55/45Glycolide/Lactide, Using Low Monofunctional Initiator Level and HighCatalyst Level

This example of an A-B block copolymer ofpoly(glycolide-co-L(−)-lactide) at an overall 90/10 glycolide/lactidemolar composition [B-segment target molar composition of 55/45glycolide/lactide] was made in the similar fashion as Example 19, basedon the teachings of U.S. Pat. No. 6,007,565, but this time the resin wasmade without dye, and with an initiator ratio (moles monomer:molesinitiator) of 1,400:1, instead of 2,800:1.

The dried resin made by this method exhibited an IV of 1.62 dL/g and aMw of 88,000 Daltons. NMR analysis confirmed that the resin contained 89mole percent polymerized glycolide and 11 mole percent polymerizedL(−)-lactide, with a residual monomer content of 0.3 mole percent. TheTg of the dried resin was 47° C., the T_(m) was 214° C., and the ΔH_(m)was 61.6 J/g as determined by DSC using the first heat scan.

Example 21 (Non-Inventive and Comparative Example to Prior Art)

Synthesis of a Segmented A-B-A Block Copolymer ofPoly(Glycolide-Co-L(−)-Lactide) at an Overall 90/10 Glycolide/LactideMolar Composition and a B-Segment Molar Composition of 50/50Glycolide/Lactide, Using Very High Catalyst Level

This example of a A-B-A block copolymer ofpoly(Glycolide-co-L(−)-lactide) at an overall 90/10 glycolide/lactidemolar composition [B-segment target molar composition of 50/50Glycolide/Lactide] was made based on the teachings of the currentinvention, except for the high catalyst concentration suggested by U.S.Pat. No. 6,007,565 (Roby et al.).

Using a large-scale 15-gallon stainless steel oil-jacketed Benco reactorequipped with agitation, 6,347 grams of glycolide and 7,881 grams ofL(−)-lactide were added along with 64.5 grams of difunctional initiator(DEG) and 36.82 ml of a 0.33M solution of stannous octoate in toluene.The dye, D&C Violet Number 2 (130 grams) was added in the mixture aswell. After the initial charge, a vacuum/nitrogen purging cycle withagitation at a rotational speed of 10 RPM in an upward direction for 20minutes was initiated. The reactor was evacuated to pressures less than250 mTorr followed by the introduction of nitrogen gas. The cycle wasrepeated once again to ensure a dry atmosphere. At the end of the finalnitrogen purge, the pressure was adjusted to be slightly above oneatmosphere and the rotational speed of the agitator was maintained at 10RPM in an upward direction. The vessel was heated by setting the oilcontroller at 185° C. After 45 minutes from initiating the heat, therotation of the agitator was switched to a downward direction. Thereaction continued for about 3.5 hours from the time the heat wasinitiated.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analytical purposes;selected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 50 mole percent polymerizedglycolide and 50 mole percent polymerized lactide with about 2 molepercent of residual unreacted monomer, mostly lactide. The DSC datarevealed that the prepolymer was fully amorphous with no crystallinitydeveloped even after heat treatment. The prepolymer (B-segment)exhibited an IV of 0.70 dL/g and a M_(w) of 28,800 Daltons.

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 215° C. and the agitator speed anddirection was set to 20 RPM in an upward direction. Once the reactortemperature and agitation was set, 50,773 grams of molten glycolidemonomer was added from a melt tank. After 10 minutes from the glycolidecharge the agitator direction was switched to forward. After 30 minutesfrom the second glycolide charge, the oil temperature was set to 207° C.for the reminder of the run. The agitator speed was reduced further at45 minutes, 90 minutes, 120 minutes, and 150 minutes from the glycolideaddition to 15, 10, 7.5, and 6.0 RPM respectively. The reactionproceeded for 165 minutes from the second glycolide charge, constitutingthe end of the final reaction period.

At the end of the final reaction period, the agitator speed was reducedto 4 RPM in the downward direction, and the polymer was discharged usingthe Gala pelletizing apparatus. The die hole size was 0.093″ with 4holes opened. The die temperature was kept at 250° C. The speed ofpelletization was 75 kg/hour, yielding 57.7 kg. Upon cooling, thepellets were placed in the freezer at −20° C. for storage for a minimumof 12 hours. After storage, the pellets were then placed into a 3-cubicfoot Patterson-Kelley tumble dryer to remove any residual monomer. Thedrying procedure was carried out exactly as described in Examples 1 and2.

The dried pellets exhibited an IV of 1.24 dL/g and a Mw of 66,200Daltons. NMR analysis confirmed that the resin contained 90 mole percentpolymerized glycolide and 10 mole percent polymerized L(−)-lactide, witha residual monomer content of 0.8 mole percent. The Tg of the driedresin was 50° C., the T_(m) was 214° C., and the ΔH_(m) was 56.0 J/g asdetermined by DSC using the first heat scan.

Example 22

Extrusion and Braiding of Prior-Art Resins Produced and Described inExamples 19, 20 and 21

Extrusion Conditions

The extrusion and orientation equipment apparatus used were the same asdescribed in Example 13. Specific extrusion and orientation conditionsand their major properties are given in Table 9A-B, and in Table 10,respectively for each of the extrudate spools and/or oriented fibersamples produced and tested. Detailed parameters used for the specificyarn samples are given for the prior art polymer samples of U.S. Pat.No. 6,007,565 as well as the best mode of this invention. Lube pump andgodet speeds were maintained at 52 rpm, and 1732 fpm, respectively foreach extrusion run.

Note that there are two types of extrusion conditions, “optimum” and“prior art”, listed in Table 9A. The “optimum” refers to the optimizedextrusion conditions that resulted in the highest mean yarn tenacitythat we could achieve with a given polymer. The “prior art” refers tothe extrusion conditions that were set using our vertical extruder asclose as possible to that taught by the prior art, i.e., U.S. Pat. No.6,007,565. The extruder barrel pressure was set at 1200 psi, with anobserved range of about 1100 to 1300 psi. The observed pump pressure wasin the range of about 2200 to about 3000 psi. The extruder screw speedranged from about 16 to 28 RPM and the melt pump from about 41 to about47 RPM.

TABLE 9A Extrusion Conditions of Prior Art Resins Produced and Describedin Examples 19, 20 and 21, as well as Conditions of the PresentInvention of the Resin Described in Example 15 Polymer Example No. 15(Inventive) 19 20 21 Extrusion Type Optimum Prior Art Prior Art OptimumPrior Art Optimum Feed Zone (° C.) 182 227 224 182 204-227 182Transition (° C.) 210 227 250 210 210-227 210 Metering (° C.) 238227-238 250 246 227 227 Pump (° C.) 249 226-246 250 254 215-227 227Block (° C.) 249 238-246 250 254 223-227 227 Spinneret (° C.) 260238-249 250 266 223-227 229 Chimney (° C.) 299-288 265 265 299 265-288288

TABLE 9B Orientation Conditions of Prior Art Resins Produced andDescribed in Examples 19, 20 and 21, as well as Conditions of thePresent Invention of the Resin Described in Example 15 Polymer ExampleNo. 15 (Inventive) 19 20 21 Extrusion Type Optimum Prior Art Prior ArtOptimum Prior Art Optimum Orientation Roll Speed (fpm) 200 200 200 200200 200 Drawing Roll Speed (fpm) 998 1148 1148 998 1148 998 Let-Off RollSpeed (fpm) 1000 1128 1128 1000 1128 1000 Orientation Roll Temp. (° C.)85 98-99 97-98 78-80 86-88 76 Drawing Roll Temp. (° C.) 120 125-132 130115 115 115 Total Draw Ratio 5.00 5.64 5.64 5.00 5.64 5.00

TABLE 10 Mean Physical Properties of 90/10 Gly/Lac Yarns Produced fromthe Resins Described in Examples 19-21, as well as the Inventive ResinDescribed in Example 15 Polymer Example No. 15 (Inventive) 19 20 21Extrusion Type Optimum Prior Art Prior Art Optimum Prior Art OptimumYarn Denier Mean 55.7 55.5 55.2 56.2 56.3 56.2 Yarn Denier Stdev 0.100.26 0.10 0.44 0.33 0.15 Mean Tenacity (gpd) 8.04 5.80 6.65 7.43 6.467.54 Tenacity Stdev 0.11 0.38 0.08 0.31 0.25 0.30 Mean Elongation (%)22.2 20.1 20.0 22.4 18.9 22.8 Elongation Stdev 0.25 1.23 0.52 0.51 0.370.47

From Table 10, for a given polymer resin (Example 20 and 21), a higheryarn tenacity with higher elongation was observed for yarn made byoptimized conditions, with a total draw ratio of about 5.0, compared tothe yarn samples using prior art conditions, which had a total drawratio of 5.64. Also, yarns produced from the inventive polymer ofExample 15 showed significantly higher mean tenacities than the yarnproduced from the non-inventive polymers of Examples 19, 20, and 21.

Braiding and Downstream Processing Summary

To produce braided suture material, yarns were first bobbin wound andbraided using a 16-carrier, 3 core construction on a New England Buttbraider. After braiding, material was skeined and solvent scoured inethyl acetate to remove lubricant finishes and foreign materialsaccumulated during upstream manufacturing steps. Using dedicatedequipment, all skeins were skein-scoured in a beaker for 15 minutes, anddrip-dried. After scouring, the skeins were then re-spooled forsubsequent hot stretching. The suture material was drawn on the heatedroll hot stretch to mechanically align the core and sheath yarns. Forthe suture size 2-0 produced, a draw ratio of 14% was used. After hotstretching, suture material was rack annealed in an annealing oven for 6hours at a temperature of 124° C.

Materials

To produce the size 2-0 braids described above, individual 56 denieryarn spools were selected from the population of yarn spools thatgenerated the mean physical properties in Table 10. The physicalproperties of the specific yarn used to produce these 2-0 braids areoutlined in Table 11.

TABLE 11 Physical Properties of the Individual 56 Denier Yarns Used toProduce Size 2-0 Braids Extrusion Tenacity Polymer ID Conditions (gpd) %Elongation Example 15 Optimized 7.82 22 Example 19 Prior art 6.28 19Example 20 Optimized 7.29 22 Prior art 6.73 20 Example 21 Optimized 7.6723 Prior art 6.79 19 Prior art 6.73 20

From Table 11, as observed in Table 10, for a given polymer resin(Example 20 and 21), a higher yarn tenacity with higher elongation wasobserved for yarn made by optimized conditions. Also, yarn produced fromthe inventive polymer of Example 15 generated higher tenacity than theyarns produced from the non-inventive polymers of Examples 19, 20, and21.

TABLE 12 Tensile Properties of Annealed 2-0 Braids Produced from PriorArt (US 6,007,565 (Roby et al.)) Resins Described in Examples 19-21, andThose of the Present Invention from Example 15 Braid Braid BraidStraight Knot Polymer Extrusion Annealed Diameter Tensile Braid %Tensile ID Conditions Braid ID (mils) S/D (lbs.) S/D Elong. S/D (lbs.)S/D Example 15 Optimized L051BSHA 12.83 0.97 18.6 0.65 17 0.94 9.28 0.38Example 19 Prior art L071BSHA 13.10 0.53 14.7 0.22 15 0.33 8.27 0.39Example 20 Optimized L069BSHA 13.42 1.03 18.4 0.46 18 0.83 9.88 0.34Prior art L070BSHA 12.83 1.05 15.9 0.39 15 0.65 9.16 0.42 Example 21Optimized L067BSHA 12.15 0.95 18.0 0.16 17 0.40 9.10 0.28 Prior artL068BSHA 12.79 0.61 17.8 0.38 15 0.66 8.87 0.33

Among samples described by prior art teachings, those braids from yarnmade by our optimized extrusion and orientation processes of the presentinvention showed slightly higher tensile properties compared to the samesamples made by the processes described previously in the prior artliterature (i.e., U.S. Pat. No. 6,007,565 (Roby et al.)).

However, the largest and the most important difference between thesamples of the present invention and those known in the prior art is intheir BSR performance as will be presented in Example 23.

Example 23

In Vitro BSR Evaluation of Annealed Braids of the Present Invention Vs.Those of Prior-Art Teachings (U.S. Pat. No. 6,007,565 (Roby et al.))Under Physiological Conditions

This example shows a clear and overwhelming difference in BSR propertiesbetween 2-0 braids made based on the present invention versus thosedescribed in the prior art teachings (U.S. Pat. No. 6,007,565).

Annealed 2-0 braids as described in Example 22 were placed in a buffersolution modelling physiological conditions of 37° C. and a pH of 7.27.Baseline (Day 0) tensile properties were measured on the suture using anInstron tensile testing unit. Additional samples were removed from thebuffer solution every 7 days and Instron tensile tested to determinetensile strength over time. Specifically, two important physicalparameters, the straight tensile strength and knot tensile strength,were monitored as a function of hydrolysis time. The Instron crossheadspeed was one inch per minute with an initial gauge length of one inch,and a 100 lb. load cell was used. For the Day 0 testing, steel faceswere used on the Instron machine, while for all other hydrolysis timesrubber faces were used to avoid slippage. After removing samples fromthe buffer baths, they were allowed to equilibrate to room temperaturebefore testing, and all samples were tested while still wet.

In FIGS. 8A-B, the straight tensile strength in percentages and pounds,respectively, was plotted against the hydrolysis time for the 2-0 braidof the present invention (Example 15), and the series of prior artbraids described in Example 22. It was unexpectedly and surprisinglyobserved that the sample of the present invention showed much longer BSRthan any of the samples described by resins and processes in the priorart. This large difference in BSR was not expected based on the initial(time zero) tensile strength values shown in Table 12, as the initialstrength values of the present invention were only slightly higher forthe sample of the present invention. This is a significant discoverythat would allow the braids of the present invention to be used insurgical applications where longer wound support is needed.

Knot tensile BSR data are shown in FIGS. 9A-B. Similarly, a dramaticdifference between the sample of the present invention (Example 15) andthe rest of 2-0 braids was observed. While for instance, in FIG. 9A, thesamples of the prior art showed the remaining knot strength percentagesbetween 0 and 5% at the 6 week interval, the samples of the presentinvention showed a significantly higher value of 30%. As in case withstraight tensile strength, this is important for surgical applicationswhere longer in vivo wound support is needed.

Additionally, size 2 braids made from the inventive polymer of Example15 were produced and also placed in a buffer solution modellingphysiological conditions of 37° C. and a pH of 7.27 to measure thestraight tensile BSR profile, using an Instron testing unit. Straighttensile strength was measured at baseline (0 days), 14 days, 28 days,and 42 days. The BSR curve of this size 2 suture is presented in FIG. 10, showing the strength loss, in pounds, over time. Greater than 25percent straight tensile strength remained after 42 days indicatingutility for slow-to-heal wound approximation.

Example 24

In Vitro/In Vivo BSR Testing and In Vivo Device Absorption

In Vitro/In Vivo BSR Testing

In Example 14 and Example 23, BSR results are presented as tested underphysiological in vitro conditions utilizing a phosphate buffer solutionof pH 7.27 and a temperature of 37° C. These in vitro conditions, orsimilar variations of, are typically used by those skilled in the art tomodel in vivo degradation of articles that degrade by hydrolysis, suchas those of the present invention. The use of in vitro testing in liueof in vivo testing is recommended to minimize the loss of animal lifewhen evaluating numerous prototypical samples.

To demonstrate how the in vitro methods described in Example 23 model invivo degradation, two different size 2-0 sutures of the presentinvention were in vitro and in vivo tested for 42-day % BSR. The twodifferent sets of size 2-0 sutures were made from the polymers ofExample 5 and Example 10, and were extruded and braided using themethods described in Example 13.

The in vivo testing was conducted by implanting the suturessubcutaneously in a rat model, and explanting the sutures at 42 days forInstron tensile testing, as described in Example 23. In vitro testingwas also conducted using the same conditions and parameters as describedin Example 23. Both sets of sutures generated differences in 42-day %BSR between in vitro and in vivo conditions of less than or equal to 2%.The results are summarized in Table 13, which demonstrate the ability ofusing a physiological in vitro method to model in vivo hydrolyticdegradation.

TABLE 13 In vitro and In vivo % BSR Results Summary for 2-0 Sutures ofthe Present Invention, made from A-B-A Polymers of Two DifferentB-Segment Compositons B-Segment Molar 2-0 Suture Composition 42-day42-day Made From (% Glycolide/ % BSR % BSR Example Number % Lactide) Invitro In vivo 10 15/85 11 10 5 60/40 30 28In Vivo Total Absorption

The sutures of the present invention were also analyzed for in vivototal absorption and tissue reaction analysis. Total absorption is ameasure of the amount of material remaining at the implantation site asa function of time. The tissue responses to the sutures of the presentinvention were comparable to a commercially available random 90/10glycolide/lactide suture at each study interval. By 119 dayspost-implantation, both sizes of the suture of the present inventionwere essentially absorbed with less than 10 percent of the suturematerial remaining in the extracellular implantation location.

Example 25

Effect of B-Segment Randomness on BSR Properties of the InventiveSutures

Two segmented A-B-A copolymers of poly(glycolide-co-L(−)-lactide) at anoverall molar composition of 90/10 glycolide/lactide [“B” segment molarcomposition of 50/50 glycolide/lactide] with similar molecular weightsbut with different randomness of comonomer distribution in the centerblock as measured by the ACSL using ¹H-NMR were prepared by the methoddescribed in Example 1. The polymer prepared with first stage reactionconditions of 192° C. for 3 hours exhibited an average sequence lengthof 2.9 whereas the polymer produced with first stage reaction conditionsof 174° C. for 2 hours exhibited an average sequence length of 3.1. Theresulting IV for both polymers was about 1.4 dL/g. Both polymers wereextruded into 56 denier yarn at a die temperature of 246° C., anorientation roll temperature of 84° C. and annealing roll temperature of115° C. Subsequently the yarn was braided into a USP size 1 braid andhot stretched at a temperature of 101° C. with a draw ratio of 16%. Thebraid was annealed for 6 hours at a temperature of 124° C. The resultingIV for both braids after annealing was 1.26 dL/g. Braided suturematerial was placed in phosphate buffer solution (pH 7.27) maintained at37° C. After 42 days, tensile strength was measured. The braid preparedfrom the polymer with an average sequence length of 2.9 had an averagetensile strength after 42 days in vitro of 11.95 pounds whereas thebraid prepared from the polymer with an average sequence length of 3.1had an average tensile strength of 11.00 pounds.

This example suggests that that the running of the first (prepolymer)stage at higher temperature at a longer time, reduces the average chainsequence length of lactoyl unit in the B-block. This, in turn, mayfurther increase the BSR of the inventive suture compositions.

Although this invention has been shown and described with respect todetailed embodiments thereof, it will be understood by those skilled inthe art that various changes in form and detail thereof may be madewithout departing from the spirit and scope of the claimed invention.

We claim:
 1. A method of making an absorbable copolymer of the structureA-B-A comprising end segments A and middle segment B, whereinend-segments A comprise polymerized glycolide and the middle segment Bcomprises polymerized glycolide and polymerized lactide, comprising thesteps of: A) forming a fully amorphous prepolymer reaction product in areactor vessel in a first stage polymerization, which will result in aprecursor to middle segment B, by polymerizing about 30 mole percent toabout 80 mole percent of polymerized lactide with about 20 mole percentto about 70 mole percent of polymerized glycolide in the presence ofdiethylene glycol as an initiator, and in the presence of a catalyst, inwhich a total reaction time of the first stage polymerization issufficient to polymerize the lactide monomer to at least 98 molepercent; B) adding additional glycolide monomer in solid or molten forminto the reaction product of the previous step, in the reactor vesselwith an agitation speed sufficient to allow complete mixing of theprepolymer and the added glycolide monomer to form a reaction mass; C)adjusting a reactor batch temperature to maintain the reaction mass inthe molten state; and, D) lowering the agitation speed and continuingthe reaction until sufficient conversion is achieved, wherein the totalamount of polymerized glycolide is about 88 mole percent to about 92mole percent of said absorbable copolymer and the amount of polymerizedlactide is about 8 mole percent to about 12 mole percent of saidabsorbable copolymer.
 2. A method of making an absorbable copolymer ofthe structure A-B-A comprising end segments A and middle segment B,wherein end-segments A comprise polymerized glycolide and the middlesegment B comprises a polymerized glycolide and lactide, comprising thesteps of: A) forming a fully amorphous prepolymer reaction product,which will result in a precursor to middle segment B, by polymerizingabout 30 mole percent to about 80 mole percent of polymerized lactideand about 20 mole percent to about 70 mole percent of polymerizedglycolide at a temperature between about 175° C. to about 195° C., inthe presence of diethylene glycol as an initiator having concentrationbetween 500:1 to 1,500:1 (mole of monomer: mole of initiator), and inthe presence of a catalyst in the total amount of 50,000:1 to 300,000:1(moles of monomer:moles of catalyst), for total reaction time of thefirst stage between 120 minutes and 180 minutes; B) adding additionalglycolide monomer in solid or molten form into the reaction product ofthe previous step in the reactor vessel with a first agitation speedsufficient to allow complete mixing of the prepolymer and addedglycolide monomer within about 30 minutes to 90 minutes; C) increasingthe reactor batch temperature up to about 205° C. to 210° C., and, D)lowering the agitation to a second agitation speed, which is about 40percent to about 70 percent lower than the first agitation speed untilsufficient conversion is achieved as measured by real-time FT-NIR remotespectroscopy, with total time of about 150 minutes to 240 minutes afterthe glycolide addition of step B above, wherein the total amount ofpolymerized glycolide is about 88 mole percent to about 92 mole percentof said absorbable copolymer and the amount of polymerized lactide isabout 8 mole percent to about 12 mole percent of said absorbablecopolymer.
 3. The method of claim 1 wherein the catalyst is stannousoctoate.
 4. The method of claim 1 wherein the catalyst level is betweenabout 100,000:1 to about 250,000:1 (moles of monomer:moles of catalyst).5. The method of claim 1 wherein the catalyst level is about 150,000:1to about 200,000:1 (moles of monomer:moles of catalyst).
 6. The methodof claim 1, wherein the catalyst is added in at least two stages: aportion of the total catalyst being added at the beginning of the firstpolymerization stage, and the rest of catalyst amount added after theglycolide monomer is sufficiently mixed with the prepolymer.
 7. Themethod of claim 1, wherein the catalyst is added in two stages: about 30percent to 60 percent of the total catalyst being added at the beginningof the first polymerization stage, and the rest of catalyst amount addedafter the second glycolide monomer addition is sufficiently mixed withthe prepolymer of the first stage.
 8. The method of claim 1, wherein thecatalyst is added in two stages: about 30 percent to 60 percent of thetotal catalyst being added at the beginning of the first polymerizationstage, and the rest of catalyst amount added about 30 minutes to 60minutes after the second glycolide monomer addition.